The present invention relates to carbapenem antibacterial agents in which the carbapenem nucleus is substituted at the 2-position with a naphthosultam linked through a CH2 group. The naphthosultam is further substituted with various substituent groups including at least one cationic group xe2x80x94Axe2x80x94Qxe2x80x94Lxe2x80x94B.
The carbapenems of the present invention are useful against gram positive microorganisms, especially methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant Staphylococcus epidermidis (MRSE), and methicillin resistant coagulase negative Staphylococci (MRCNS), and are also active against Gram negative bacteria. There is an increasing need for agents effective against such pathogens (MRSA/MRCNS) which are at the same time relatively free from undesirable side effects. The antibacterial compounds of the present invention thus comprise an important contribution to therapy for treating infections caused by these difficult to control pathogens.
The compounds of the invention are represented by formula I: 
as well as pharmaceutically acceptable salts thereof, wherein:
R1 represents H or methyl;
CO2M represents a carboxylic acid, a carboxylate anion, a pharmaceutically acceptable ester group or a carboxylic acid protected by a protecting group;
P represents hydrogen, hydroxyl, F or hydroxyl protected by a hydroxyl-protecting group;
Axe2x80x94Qxe2x80x94Lxe2x80x94B represents a side chain wherein:
A is a C1-6 alkylene group, straight or branched, and optionally interrupted or terminated by 1-2 of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, NRaxe2x80x94, xe2x80x94C(O)xe2x80x94 and xe2x80x94CHxe2x95x90CHxe2x80x94;
Q is selected from: 
xe2x80x83in which:
a is 1, 2 or 3;
b is 2 or 3;
and Xxe2x88x92 is a monovalent or divalent charge balancing counterion;
L represents a bond or a C1-8 alkylene group, unsubstituted or substituted with 1-3 Rc groups, uninterrupted, interrupted or terminated by 1-3 of xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NRdxe2x80x94, xe2x80x94Het(Re)xe2x80x94, xe2x80x94C(O)xe2x80x94Het(Re)xe2x80x94, xe2x80x94C(O)NRaxe2x80x94Het(Re)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94NRaxe2x80x94, xe2x80x94N+(Ra)2xe2x80x94, 
Het is a heteroaryl group;
B represents a member selected from the group consisting of: 
4) a 4-7 membered, N-containing heterocycle selected from: 
wherein c and d are independently 0-4, such that c+d equals from 2-5, and said heterocycle is optionally substituted on carbon atoms with 1-2 Rf or Rg groups, and is optionally interrupted by O, S, NRf or NRg; 
wherein 
xe2x80x83and 
xe2x80x83represent quaternary an d non-quaternary 5-10 membered mono- or bicyclic, N-containing heteroaryl groups, respectively, optionally containing 1-4 additional heteroatoms selected from O, S and N; and 
Ra is H or C1-6 alkyl;
Rb is independently selected from NH2 and C1-6 alkyl unsubstituted or substituted with 1-3 groups selected from halo, OH, CN and C(O)NH2;
Rc is independently selected from halo, ORa, SRa, OC(O)Ra, CO2Ra, CN, C(O)N(Ra)2 and C(O)Ra,
Rd is H or C1-3 alkyl, or Rc and Rd taken together with any intervening atoms represent a 4-6 membered ring;
Re is H; Rc; NO2, N(Ra)2, SO2N(Ra)2 or C1-4 alkyl, unsubstituted or substituted with 1-3 groups selected from halo, OH and C(O)NH2
Rf, Rg and Rh are independently selected from H; C1-6 straight or branched chain alkyl, unsubstituted or substituted with 1-3 Rc groups; C3-6 cycloalkyl, unsubstituted or substituted with 1-3 Rc groups; phenyl, unsubstituted or substituted with 1-3 Re groups and Het, unsubstituted or substituted with 1-3 Re groups, or
Rf and Rg taken together with the intervening N atom form a 4-6 membered ring, optionally interrupted by 1-2 of O, S, C(O) or NRh, and optionally substituted by 1-3 Rc groups;
Ri is H or Rb;
Rj and Rk are C1-4 alkyl or Rj and Rk taken together with the intervening S atom are a 5-6 membered ring;
and each R independently represents H; Rc; NO2; N(Ra)2; SO2N(Ra)2 or C1-4 alkyl, unsubstituted or substituted with 1-3 groups selected from halo, OH and C(O)NH2, or
R together with A of the group xe2x80x94Axe2x80x94Qxe2x80x94Lxe2x80x94B and any intervening atoms represent a 5-6 membered carbocyclic ring.
Pharmaceutical compositions and methods of treatment are also included.
The invention is described herein in detail using the terms defined below unless otherwise specified.
Carboxylate anion refers to a negatively charged group xe2x80x94COOxe2x80x94.
The term xe2x80x9calkylxe2x80x9d refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 15 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopentyl and cyclohexyl. When substituted, alkyl groups may be substituted with up to four substituent groups, selected from Rc, Rf and Rg, or as otherwise defined, at any available point of attachment. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with xe2x80x9cbranched alkyl groupxe2x80x9d.
Cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings which are fused.
The term xe2x80x9calkenylxe2x80x9d refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.
The term xe2x80x9calkynylxe2x80x9d refers to a hydrocarbon radical straight or branched, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond. Preferred alkynyl groups include ethynyl, propynyl and butynyl.
Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and the like, as well as rings which are fused, e.g., naphthyl, phenanthrenyl and the like. An aryl group thus contains at least one ring having at least 6 atoms, with up to five such rings being present, containing up to 22 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms. The preferred aryl groups are phenyl, naphthyl and phenanthrenyl. Aryl groups may likewise be substituted as defined. Preferred substituted aryls include phenyl and naphthyl.
The term xe2x80x9cheteroarylxe2x80x9d (Het) refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, and in which 1-2 additional carbon atoms are optionally replaced by a heteroatom selected from O or S, and in which from 1-3 additional carbon atoms are optionally replaced by N, said heteroaryl group being optionally substituted as described herein. Examples include the following: 
Heteroaryl includes protonated forms as well. It thus includes positively charged as well as non-charged groups. Examples include the groups shown above, having an additional H attached to a nitrogen atom.
The group Axe2x80x94Qxe2x80x94Lxe2x80x94B is attached to one of the two phenyl rings shown.
Heteroarylium refers to heteroaryl groups bearing a quaternary or protonated atom and thus a positive charge. Examples include the following: 
When a charge is shown on a particular nitrogen atom in a ring or in a nitrogen containing non-ring moiety which contains one or more additional nitrogen atoms, it is understood that the charge may reside on a different nitrogen atom than that shown in a particular drawing by virtue of charge resonance that occurs. 
For example, 
Likewise, when a basic nitrogen containing moiety is provided at an appropriately acidic pH, the moiety becomes protonated due to acid base reactivity. Both the protonated and non-protonated forms of the compounds of formula I are included in the present invention.
The term xe2x80x9cheterocycloalkylxe2x80x9d refers to a cycloalkyl group (nonaromatic) in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S or N, and in which up to three additional carbon atoms may be replaced by hetero atoms.
The terms xe2x80x9cquaternary nitrogenxe2x80x9d and xe2x80x9cpositive chargexe2x80x9d refer to tetravalent, positively charged atoms including, e.g., the positively charged nitrogen in a tetraalkylammonium group (e. g. tetramethylammonium), heteroarylium, (e.g., N-methyl-pyridinium), basic nitrogens which are protonated at physiological pH, and the like. Cationic groups thus encompass positively charged nitrogen-containing groups, as well as basic nitrogens which are protonated at physiologic pH.
The term xe2x80x9cheteroatomxe2x80x9d means O, S or N, selected on an independent basis.
Halogen and xe2x80x9chaloxe2x80x9d refer to bromine, chlorine, fluorine and iodine.
Alkoxy refers to C1-C4 alkyl-Oxe2x80x94, with the alkyl group optionally substituted as described herein.
When a group is termed xe2x80x9csubstitutedxe2x80x9d, unless otherwise indicated, this means that the group contains from 1 to 4 substituents thereon.
When a functional group is termed xe2x80x9cprotectedxe2x80x9d, this means that the group is in modified form to preclude undesired side reactions at the protected site. Suitable protecting groups for the compounds of the present invention will be recognized from the present application taking into account the level of skill in the art, and with reference to standard textbooks, such as Greene, T. W. et al. Protective Groups in Organic Synthesis Wiley, New York (1991). Examples of suitable protecting groups are contained throughout the specification.
In some of the carbapenem compounds of the present invention, M is a readily removable carboxyl protecting group, and/or P represents a hydroxyl which is protected by a hydroxyl-protecting group. Such conventional protecting groups consist of groups which are used to protectively block the hydroxyl or carboxyl group during the synthesis procedures described herein. These conventional blocking groups are readily removable, i.e., they can be removed, if desired, by procedures which will not cause cleavage or other disruption of the remaining portions of the molecule. Such procedures include chemical and enzymatic hydrolysis, treatment with chemical reducing or oxidizing agents under mild conditions, treatment with a transition metal catalyst and a nucleophile and catalytic hydrogenation.
Examples of carboxyl protecting groups include allyl, benzhydryl, 2-naphthylmethyl, benzyl, silyl such as t-butyldimethylsilyl (TBDMS), phenacyl, p-methoxybenzyl, o-nitrobenzyl, p-methoxyphenyl, p-nitrobenzyl, 4-pyridylmethyl and t-butyl.
Examples of suitable hydroxyl protecting groups include triethylsilyl, t-butyldimethylsilyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl and the like.
The carbapenem compounds of the present invention are useful per se and in their pharmaceutically acceptable salt and ester forms for the treatment of bacterial infections in animal and human subjects. The term xe2x80x9cpharmaceutically acceptable ester, salt or hydrate,xe2x80x9d refers to those salts, esters and hydrated forms of the compounds of the present invention which would be apparent to the pharmaceutical chemist. i.e., those which are substantially non-toxic and which may favorably affect the pharmacokinetic properties of said compounds, such as palatability, absorption, distribution, metabolism and excretion. Other factors, more practical in nature, which are also important in the selection, are cost of the raw materials, ease of crystallization, yield, stability, solubility, hygroscopicity and flowability of the resulting bulk drug. Conveniently, pharmaceutical compositions may be prepared from the active ingredients in combination with pharmaceutically acceptable carriers. Thus, the present invention is also concerned with pharmaceutical compositions and methods of treating bacterial infections utilizing as an active ingredient the novel carbapenem compounds.
With respect to xe2x80x94CO2M, which is attached to the carbapenem nucleus at position 3, this represents a carboxylic acid group (M represents H), a carboxylate anion (M represents a negative charge), a pharmaceutically acceptable ester (M represents an ester forming group) or a carboxylic acid protected by a protecting group (M represents a carboxyl protecting group). The pharmaceutically acceptable salts referred to above may take the form xe2x80x94COOM, where M is a negative charge, which is balanced by a counterion, e.g., an alkali metal cation such as sodium or potassium. Other pharmaceutically acceptable counterions may be calcium, magnesium, zinc, ammonium, or alkylammonium cations such as tetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium, meglumine, triethanolhydroammonium, etc.
The pharmaceutically acceptable salts referred to above also include acid addition salts. Thus, the Formula I compounds can be used in the form of salts derived from inorganic or organic acids. Included among such salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.
The pharmaceutically acceptable esters are such as would be readily apparent to a medicinal chemist, and include, for example, those described in detail in U.S. Pat. No. 4,309,438. Included within such pharmaceutically acceptable esters are those which are hydrolyzed under physiological conditions, such as pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, and others described in detail in U.S. Pat. No. 4,479,947. These are also referred to as xe2x80x9cbiolabile estersxe2x80x9d.
Acid addition salts of the compounds of formula I are likely protonated at physiological pH, as mentioned above. Compounds such as those containing a basic N-containing moiety are capable of protonation in water at or near pH 7, so that the moiety can exist in its neutral form or as an acid addition (protonated) form.
Xxe2x88x92 is a charge balancing group.
For the purposes of this invention, all compounds which have one or more cations are balanced with one or more, as necessary, of a charge balancing group Xxe2x88x92. Examples of cases where a charge balancing group is required are quarternized substituents such as heteroarylium. Additionally, all compounds having one or more anions are counter balanced with one or more, as necessary, charge balancing counterions.
When a group is interrupted by 2-3 of O, S, or N they cannot form Oxe2x80x94O, Oxe2x80x94Oxe2x80x94O, Oxe2x80x94S, Oxe2x80x94Sxe2x80x94O, Sxe2x80x94S, or Sxe2x80x94Sxe2x80x94S bonds. This is exemplified in the case when A is an alkylene interrupted or terminated by 1-2 of O, S, NRa, . . . and the like.
Biolabile esters are biologically hydrolizable, and may be suitable for oral administration, due to good absorption through the stomach or intenstinal mucosa, resistance to gastric acid degradation and other factors. Examples of biolabile esters include compounds in which M represents an alkoxyalkyl, alkylcarbonyloxyalkyl, alkoxycarbonyloxyalkyl, cycloalkoxyalkyl, alkenyloxyalkyl, aryloxyalkyl, alkoxyaryl, alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, arylthioalkyl or alkylthioaryl group. These groups can be substituted in the alkyl or aryl portions thereof with acyl or halo groups. The following M species are examples of biolabile ester forming moieties: acetoxymethyl, 1-acetoxyethyl, 1-acetoxypropyl, pivaloyloxymethyl, 1-isopropyloxycarbonyloxyethyl, 1-cyclohexyloxycarbonyloxyethyl, phthalidyl and (2-oxo-5-methyl-1,3-dioxolen-4-yl)methyl.
Xxe2x88x92 can be present or absent as necessary to maintain the appropriate charge balance. When present, these represent pharmaceutically acceptable counterions. Most anions derived from inorganic or organic acids are suitable. Representative examples of such counterions are the following: acetate, adipate, aminosalicylate, anhydromethylenecitrate, ascorbate, aspartate, benzoate, benzenesulfonate, bromide, citrate, camphorate, camphorsulfonate, chloride, estolate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glutamate, lactobionate, malate, maleate, mandelate, methanesulfonate, pantothenate, pectinate, phosphate/diphosphate, polygalacturonate, propionate, salicylate, stearate, succinate, sulfate, tartrate and tosylate. Other suitable anionic species will be apparent to the ordinarily skilled chemist.
Likewise, when more than one negative charge is necessary to maintain charge neutrality, the counterion indicator Xxe2x88x92 represents a specie with more than one negative charge, such as malonate, tartrate or ethylenediaminetetraacetate (EDTA), or when a multivalent negatively charged counterion is present with a carbapenem which bears a net single positive charge, an appropriate number of carbapenem molecules can be found in association therewith to maintain the overall charge balance and neutrality.
Numbering and nomenclature using in naming the naphthosultams are as follows: 
The xe2x80x94Axe2x80x94 portion of the side chain is a C1-6 alkylene group which is straight or branched, and is optionally interrupted or terminated by 1-2 of O, S, NRa, C(O), and xe2x80x94CHxe2x95x90CHxe2x80x94. The interrupting groups can be separate or together, and can terminate the C1-6 alkylene group. Also, the interrupting or terminating moiety can be between the alkylene group and the naphthosultam or xe2x80x94Qxe2x80x94. For example, A can represent xe2x80x94Oxe2x80x94C1-6 alkylxe2x80x94, xe2x80x94C1-6 alkyl xe2x80x94Oxe2x80x94, xe2x80x94NRaxe2x80x941-6 alkylxe2x80x94 and the like.
The variable L represents a bond or a C1-8 alkylene group, which is unsubstituted or substituted with 1-3 Rc groups. The C1-8 alkylene moiety can be interrupted or terminated by 1-3 of the following:
xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NRdxe2x80x94, xe2x80x94Het(Re)xe2x80x94, xe2x80x94C(O)xe2x80x94Het(Re)xe2x80x94, xe2x80x94C(O)NRaxe2x80x94Het(Re)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94CO2xe2x80x94, 
These interrupting or terminating moieties can be separate or together. As described above with respect to A, the moieties can be at the ends of the C1-8 alkylene group, and between the C1-8 alkylene moiety and Q or B.
B can be selected from groups 1)-6) shown above. These include positively charged as well as neutral moieties, many of which become positively charged at neutral to acidic pH. All are included in the present invention.
When Rb represents C1-6 alkyl, it may be unsubstituted or substituted with 1-3 groups selected from halo, OH, CN and C(O)NH2.
When Rc and Rd both appear, they may be taken in combination with any intervening atoms to form a 4-6 membered ring.
When Rf and Rg are both present, they can be taken together with the intervening atoms to form a 4-6 membered ring, which is optionally interrupted by 1-2 of O, S, C(O) and NRh. The ring can be unsubstituted or substituted with 1-3 Rc groups.
When Rj and Rk are taken together with the S atom, they represent a 5-6 membered ring.
When one of the R groups is taken in combination with A from the side chain Axe2x80x94Qxe2x80x94Lxe2x80x94B, along with the intervening atoms, it represents a 5-6 membered carbocyclic ring.
A subset of compounds of formula I which is of interest relates to those compounds where R1 represents methyl. Within this subset, all other variables are as originally defined.
Another subset of compounds of formula I which is of interest relates to those compounds where CO2M represents a carboxylate anion. Hence, M in this instance represents a negative charge which is balanced by a positively charged group, such as in the positively charged Q group. Likewise, if the positively charged Q group contains more than one positive charge, a negatively charged counterion may be present which in combination with the carboxylate anion, provides overall charge neutrality.
Another subset of compounds of formula I that is of interest relates to those compounds where P represents hydroxyl or hydroxyl protected by a hydroxyl protecting group. Within this subset, all other variables are as originally defined.
Another subset of compounds of formula I that is of interest relates to compounds of formula I wherein A represents C1-3 alkylene. Within this subset, all other variables are as originally defined.
Another subset of compounds of formula I that is of interest relates to compounds where Q represents 
wherein Xxe2x88x92 represents a charge balancing group. Within this subset, all other variables are as originally defined.
Another subset of compounds of formula I that is of interest relates to compounds where L is a bond or C1-5 alkylene, optionally interrupted or terminated by xe2x80x94C(O)NRdxe2x80x94, xe2x80x94C(O)NRaHet(Re)xe2x80x94, xe2x80x94NRaxe2x80x94, xe2x80x94N+(Ra)2 or 
Within this subset, all other variables are as originally defined.
Another subset of compounds of formula I that is of interest relates to compounds where B is selected from: 
4) a 4-7 membered, N-containing heterocycle selected from: 
xe2x80x83wherein c and d are independently 0-4, such that c+d equals from 2-4, and said heterocycle is optionally substituted on carbon atoms with 1-2 Rf or Rg groups, and is optionally interrupted by NRf or NRg; and
5) 
xe2x80x83wherein 
represents a quaternary 5-10 membered mono- or bicyclic, N-containing heteroaryl group, optionally containing 1-4 additional heteroatoms selected from O, S and N. Within this subset, all other variables are as originally defined.
A preferred subset of compounds of formula I which is of interest relates to those compounds wherein:
R1 represents methyl;
CO2M represents a carboxylate anion;
P represents hydroxyl or hydroxyl protected by a hydroxyl protecting group;
A represents C1-3 alkylene;
Q represents 
xe2x80x83wherein Xxe2x88x92 represents a charge balancing;
L represents a bond or C1-5 alkylene, optionally interrupted or terminated by xe2x80x94C(O)NRdxe2x80x94, xe2x80x94C(O)NRaxe2x80x94Het(Re)xe2x80x94, xe2x80x94NRaxe2x80x94, xe2x80x94N+(Ra)2
B is selected from: 
4) a 4-7 membered, N-containing heterocycle selected from: 
xe2x80x83wherein c and d are independently 0-4, such that c+d equals from 2-4, and said heterocycle is optionally substituted on carbon atoms with 1-2 Rf or Rg groups, and is optionally interrupted by NRf or NRg; and
5) 
xe2x80x83wherein 
represents a quaternary 5-10 membered mono- or bicyclic, N-containing heteroaryl group, optionally containing 1-4 additional heteroatoms selected from O, S and N, and all other variables are as originally defined.
Representative examples of compounds of the invention are found in Tables I-III.
The process is illustrated by the following generic scheme: 
With reference to Flow Sheet A above, P, R1, R, and M, are as defined with respect to the compounds of formula I.
P** represents a carboxyl protecting group.
Q*xe2x80x94Lxe2x80x94Bxe2x80x2 represents a group which reacts with intermediate A2 (upon activation of A2) in a manner which results in the incorporation in the final product of a member of the group defined as Qxe2x80x94Lxe2x80x94B above, thus Q*xe2x80x94Lxe2x80x94Bxe2x80x2 may be viewed as a precursor for Qxe2x80x94Lxe2x80x94B.
The naphthosultam side chain group used in the synthesis of the compounds of the present invention have, in some cases, been described in the chemical literature. In other cases, precursor compounds which may be readily converted to the requisite naphthosultam have been described in the literature. In cases where the requisite naphthosultam is not known in the literature it is neceessary to synthesize the naphthosultam by a newly developed synthesis. One skilled in the art can adapt a previously published synthesis of an analogous naphthosultam to prepare the requisite compound in a straightforward manner without undue experimentation. Examples of naphthosultam synthesis are described herein (see below).
The naphthosultam side chain group is initially reacted with a suitably protected carbapen-2-em-3-carboxylate having an activated hydroxymethyl group at the 2-position.
The carbapenem nucleus having a xe2x80x94CH2OH substituent at position 2 can be obtained in accordance with Schmitt, S. M. et al., J. Antibiotics 41(6): 780-787 (1988), the teachings of which are incorporated herein by reference. The carboxylic acid group at C-3 of the carbapenem is generally protected as a carboxyl protecting group such as p-nitrobenzyl (PNB), allyl, p-methoxybenzyl, trichloroethyl, 2-trimethylsilylethyl, and the like. Furthermore, the hydroxyl group of the 6-(hydroxyethyl) side-chain is optionally protected with a hydroxyl protecting group such as trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl, allyloxycarbonyl, 2-trimethylsilylethoxy carbonyl, 2-trichloroethoxycarbonyl and the like.
The addition of the naphthosultam side chain group to the carbapenem is accomplished by treating a solution of the hydroxymethyl-carbapenem and the naphthosultam side chain group in a suitable solvent such as tetrahydrofuran (THF), ether, acetonitrile, dimethylformamide (DMF), benzene, dimethylsulfoxide (DMSO), and the like with a (premixed) suitable activating reagent such as diethyl azodicarboxylate (DEAD)/triphenylphosphine, diisopropyl azodicarboxylate (DIAD)/tributylphosphine, and the like, at a temperature between about xe2x88x9220xc2x0 C. and 35xc2x0 C. for about 5 to 90 minutes.
Alternatively, the naphthosultam and carbapenem can be mixed together with either the azodicarboxylate or the phosphine reagent in a suitable solvent and the other component of the activating reagent (the phosphine or the azodicarboxylate, respectively) can be added to that mixture. Once the naphthosultam, carbapenem, and activating reagent(s) have been mixed, the reaction is allowed to proceed at a temperature between about xe2x88x9220xc2x0 C. and 35xc2x0 C. for about 5 to 90 minutes.
The resulting mixture is then subjected to a standard work-up procedure familiar to those skilled in the art to afford a crude 2-naphthosultam-methyl substituted carbapenem which is purified, if necessary, by recrystallization or by chromatography on silica gel, eluting with a suitable solvent or mixture of two or more solvents, such as hexane, ethyl acetate, ether, benzene, dichloromethane, chloroform, acetone, methanol and the like.
Modification of the naphthosultam side chain of compounds A2, which is generally necessary to introduce the charged substituent of A4, is best accomplished before removal of the protecting groups. For compounds which contain a hydroxyl group (Xxe2x80x2) in the side chain, a positively charged substituent may be introduced into the side chain by first activating the hydroxyl group by converting it to a suitable leaving group (X) such as a triflate, mesylate, tosylate, iodide, chloride, bromide, and the like, and then displacing the resulting leaving group with a compound Q*, such as a suitably substituted diazabicyclooctane or a suitably substituted N,N-dimethylpiperazine. Alternatively, in some cases, the charged substituent may be incorporated in the naphthosultam side chain before addition of the naphthosultam to the carbapenem or may be introduced after deprotection of A2. However, introduction of the charged substituent by modification of A2 before deprotection is greatly preferred.
In some cases, activation of the hydroxyl group and displacement by Q* to produce A3 may be accomplished in a single step by taking advantage of the basic character of compound Q* and using it as a base in the activation reaction.
The conversion of the hydroxyl group to a suitable leaving group is accomplished by treating the hydroxyl substituted compound in a suitable solvent such as dichloromethane, tetrahydrofuran, ether, benzene, and the like with an activating reagent, such as trifluoromethanesulfonic anhydride, methanesulfonic anhydride, toluenesulfonic anhydride, methanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, and the like in the presence of a suitable base such as triethylamine, tributylamine, diisopropylethyl-amine, and the like at a temperature between about xe2x88x92100xc2x0 C. and 0xc2x0 C. for about 5 to 120 minutes. The intermediate thus obtained contains a leaving group, which may be converted to an alternative leaving group, iodide, by treating a solution of the intermediate in a suitable solvent such as acetone, methyl ethyl ketone, and the like at about xe2x88x9210xc2x0 C. to 50xc2x0 C. with an excess of sodium iodide or potassium iodide for about 0.25 to 24 hours.
In many cases, the iodide is obtained in sufficiently pure form that it may be used without further purification. For ease of handling, the iodide, if not crystalline, may be lyophilized from benzene to afford an amorphous, easily handled, solid.
The activated hydroxyl group or iodide is displaced by reacting the activated intermediate with reagent Q*. In some cases, activation and displacement of the hydroxyl group may be accomplished in a single step. The activating reagent is added to a solution of the hydroxyl substituted compound in the presence of a suitable base in a suitable solvent such as dichloromethane, tetrahydrofuran, ether, DMF, benzene, acetonitrile, DMSO, and the like as described in the preceding paragraphs. The resulting activated intermediate is treated with 1-3 molar equivalents of compound Q* at a temperature between about xe2x88x9278xc2x0 C. and 50xc2x0 C. for about 15 to 120 minutes. In some cases, it is desirable to form the activated intermediate in one solvent, isolate the activated intermediate, and conduct the displacement reaction in a different solvent. In other cases, the displacement may be conducted without isolation of the intermediate and, in cases where Q* is also used as a base, may even be concurrent with the formation of the activated intermediate.
In cases where the displacement reaction is best accomplished by using the iodide, a solution of the iodide is combined with an approximately equivalent amount (0.9-1.05 molar equivalents) of compound Q*. A silver salt of a non-nucleophilic acid, such as silver trifluoromethanesulfonate, silver tetrafluoroborate and the like is then added. Although the reaction will proceed in the absence of the silver salt, the reaction proceeds more rapidly in the presence of the silver salt. In addition, the silver salt assists in the removal of the displaced iodide from the reaction mixture which can improve the efficiency of subsequent steps. The resulting mixture is then subjected to a standard work-up procedure familiar to those skilled in the art to afford a crude product which is purified, if necessary, by recrystallization or chromatography.
The synthesis of the target compound is completed by removing any protecting groups which are present in the penultimate intermediate using standard techniques which are well known to those skilled in the art. The deprotected final product is then purified, as necessary, using standard techniques such as ion exchange chromatography, HPLC on reverse phase silica gel, MPLC on reverse phase polystyrene gel, and the like or by recrystallization.
The final product may be characterized structurally by standard techniques such as NMR, IR, MS, and UV. For ease of handling, the final product, if not crystalline, may be lyophilized from water to afford an amorphous, easily handled solid.
The compounds of the present invention are valuable antibacterial agents active against various Gram-positive and Gram-negative bacteria, and accordingly find utility in human and veterinary medicine.
Many of compounds of the present invention are biologically active against MRSA/MRCNS. In vitro antibacterial activity is predictive of in vivo activity when the compounds are administered to a mammal infected with a susceptible bacterial organism.
Using standard susceptibility tests, the compounds of the invention are determined to be active against MRSA.